The Genetics of otosclerosis

Abstract

Otosclerosis is a common form of conductive hearing loss with a prevalence of 0.3–0.4% in white adults. It is characterized by labyrinthine endochondral sclerosis which may invade the stapedio-vestibular joint and interfere with free motion of the stapes. Both environmental factors and genetic causes have been implicated in the disease process; however, the pathogenesis of otosclerosis still remains poorly understood. To date, several loci have been mapped in families segregating autosomal dominant otosclerosis although no disease-causing mutations have been identified. In contrast, several association studies have implicated specific genes but their effects on risk-of-disease are small. The goal of this paper is to review the genetics of otosclerosis and to provide insight into studies that could be performed to elucidate disease pathogenesis.

Introduction

Otosclerosis is a disease of the bony labyrinth of the inner ear caused by abnormal remodeling in the otic capsule, most commonly just anterior to the stapedio-vestibular joint in the area of the fissula ante fenestram (Nager, 1969). If the stapedio-vestibular joint becomes involved, free motion of the stapes is compromised and a conductive hearing loss results.

The otic capsule normally undergoes very little bone remodeling after development with a bone turn-over rate of approximately 0.13% per year as compared to the rest of the skeleton, which turns over at a rate of approximately 10% per year (Frisch et al., 2000). The otic capsule is also unique in that it has foci of residual embryonic material called globuli interossei, which contain quiescent osteocytes and chondrocytes (Schuknecht, 1993). Whether these unique features are significant in the development of otosclerosis is not known.

The clinically relevant form of otosclerosis, which results in measurable hearing loss, affects 0.3–0.4% of the Caucasian population (Declau et al., 2001). Average age of onset is in the third decade, although the range extends from the late teenage years to the 6th decade. Bilateral disease occurs in 70–80% of persons. Surgical treatment in which the suprastructure of the stapes is removed and replaced by a piston-like cylindrical prosthesis that projects through a small opening in the oval window into the vestibule of the inner ear is typically effective in improving hearing.

Otosclerotic lesions are also found in temporal bone analysis postmortem in persons with normal hearing. These lesions, known as histologic otosclerosis, occur in up to 12.5% of the Caucasian population (Declau et al., 2007). At the other extreme, approximately 10% of patients with clinical otosclerosis develop sensorineural hearing loss secondary to involvement of the bony capsule immediately surrounding the cochlea (Browning and Gatehouse, 1984, Ramsay and Linthicum, 1994).

The frequency of otosclerosis as a common cause of hearing loss was first recognized in the late 19th century by Politzer (1894). Eighteen years later, the active form of the disease was described by Siebenmann (1912). This stage, characterized by highly vascularized regions of the otic capsule that contain activated macrophages and osteoclasts, is referred to as otospongiosis. The later stages of otosclerosis include new bone deposition, which can be replaced by fibrous tissue, and the formation of dense sclerotic bone (Schuknecht, 1993). Despite efforts to identify environmental and genetic factors involved in this process, disease pathophysiology remains poorly understood. In this review, we will focus on the genetic contributions to otosclerosis, emphasizing studies that could be undertaken to elucidate disease pathogenesis.